1. Technical Field of Invention
The present invention embodiments relate to novel 4-(indol-3-yl)-pyrazole derivatives, including pharmaceutically acceptable enantiomers, salts and solvates thereof. Compounds of certain embodiments of the invention are inhibitors of TDO2 (tryptophan 2,3-dioxygenase) and are useful as therapeutic compounds, particularly in the treatment and/or reduction in the likelihood of occurrence of and/or prevention of cancers.
2. Description of the Related Art
Two decades after the importance of tryptophan catabolism for maintaining the immune privilege of the placenta was discovered (Munn, D. H. et al., Science, 1998, 281, 1191-1193), increasing evidence is extending its biological relevance beyond immune tolerance to non-self. According to the generally accepted concept, tryptophan, an essential amino acid, is catabolized in the local microenvironment of tumors, immune-privileged sites, or sites of inflammation (Mellor A L and Munn D H., Nat Rev Immunol, 2008, 8, 74-80). In these tissues, cancer cells, immune cells, or specialized epithelial cells (e.g., syncytiotrophoblasts in the placenta) create an immunosuppressive environment in tumors that shut down antitumor immune responses in tumors and in tumor-draining lymph nodes by inducing T-cell anergy and apoptosis through depletion of tryptophan and accumulation of immunosuppressive tryptophan catabolites (Munn D H et al., J Exp. Med., 1999, 189, 1363-1372; Fallarino F et al., Cell Death Differ., 2002, 9, 1069-1077).
It has now been discovered that a key enzyme in tryptophan catabolism, tryptophan 2,3-dioxygenase (TDO2), which is considered responsible for regulating systemic tryptophan levels in the liver, is constitutively expressed in some cancers. TDO2 expression in tumor cells prevents tumor surveillance by the immune system and thus prevents tumor rejection by locally degrading tryptophan (Opitz C A et al., Nature, 2011, 478(7368), 197-203). In addition, inhibition of TDO2 by a small molecule prevents tumor growth in animal models for immunotherapy (Pilotte L et al., Proc Natl Acad Sci USA, 2012, 109(7), 2497-502).
The tryptophan catabolism in some cancers might be also increased by the expression of indoleamine 2,3-dioxygenase (IDO) by tumor cells (Uyttenhove, C. et al., Nat. Med., 2003, 9, 1269-1274).
Because tryptophan catabolism is induced by inflammatory mediators, notably IFN-gamma, it is thought to represent an endogenous mechanism that restricts excessive immune responses, thereby preventing immunopathology. In the context of cancer, this feedback loop may not be beneficial, as tryptophan catabolism has been implicated in inflammation-driven cancers such as colon cancer (Muller A J et al., Proc Natl Acad Sci USA, 2008, 105, 17073-8). There is strong evidence that suppression of antitumor immune responses in precancerous lesions and established cancers by tryptophan catabolism promotes tumor growth, which would make such catabolism an attractive target for therapeutic intervention (Dolugie E and Frederick R., Expert Opin Ther Pat., 2013, 23(10), 1367-81). Hence, a considerable effort is being made to identify selective and efficient inhibitors of tryptophan catabolism to enhance the efficacy of conventional chemotherapy, immune checkpoints (Holmgaard R B et al., J Exp Med., 2013, 210(7), 1389-402) or therapeutic vaccines.
Some TDO2 inhibitors were proposed in WO2010/008427 and by Dolusic, E. et al. (Dolusic et al., J. Med. Chem., 2011, 54, 5320-5334), however either their affinity for the target is limited, or their pharmacokinetic properties are not suitable for development as a drug for human use.
Therefore, there is a need for new TDO2 inhibitors with improved efficacy for treating and/or reducing the likelihood of occurrence of cancer and/or for cancer prevention. The present invention provides according to certain herein disclosed embodiments new TDO2 inhibitors which may be administered to any patient diagnosed with cancer, or to any subject being at risk of developing a cancer.